Download Principles of Toxicology

CLASS: 10:00 – 11:00
DATE: December 10, 2010
PROFESSOR: Smith
I.
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VII.
PRINCIPLES OF TOXICOLOGY
Scribe: Adam Baird
Proof:
Page 1 of 5
PRINCIPLES OF TOXICOLOGY [S1]
a. We’ll talk about some of the classic toxic agents that have been studied.
1. The reason we’ll talk about those classic toxic agents (like cyanide, carbon monoxide,
acetaminophen) is because they illustrate the principles of toxicology. Besides the obvious medical
relevance, theses examples also emphasize the value of understanding the mechanism of action of
the poison. Knowing the mechanism, then, is the foundation for developing an antidote and
assessing risk.
b. We’ll talk about some toxic metals too (like arsenic, lead, mercury).
1. Mercury has particular relevance to the dentistry profession (because of the risk associated with the
use of mercury used in fillings). The mercury fillings are long lasting and they work well though,
which is why it is difficult to pursue changes. Evidence in the last decade suggests that the mercury
is not completely inert (meaning that some of the mercury in the filling is mobilized, especially when
the filling is on the grinding surface of a molar, for example).
c. Finally, we’ll talk about the anticdote that is used to treat metal poisoning.
1. This is a class of drugs called chelaters. We’ll talk specifically about the succimer drug, which is an
important drug for treating metal poisoning (which is a major public health concern). Arsenic, lead,
and mercury are considered to be the 3 major poisons associated with the “superfun” sites (a site
that has to be isolated or contained so that the public is not continually poisoned by its products).
“ALL SUBSTANCES ARE POISONS…” [S2]
a. Paracelsus recognized that “al substances are poisons” and that it is simply the dose that differentiates a
poison from a remedy.
NO TITLE [S3]
a. A metal as poisonous as mercury, for example, has some therapeutic benefit.
b. Water, as necessary as it is for human life, can be overdosed on.
c. So, the most important thing to do: assess the risks and understand the relationship between the dose of a
drug or exposure to a toxic agent and the toxic effect that is produced.
d. It’s important to understand, then, the molecular mechanism of action.
DOSE EFFECT: GRADED VS. QUANTAL [S4]
a. This is a quantal dose effect diagram on a log scale. It indicates how you would determine the lethal dose of a
substance.
b. Notice that both compounds (A and B) have the same lethal dose. Compound A, at lower doses (below
LD50), produces significantly more lethality than Compound B.
c. When reviewing this diagram, it’s important to note the slope of the line.
> 109 FOLD RANGE IN LETHALITY [S5]
a. There is a huge range of LD50s for various compounds.
TOXICITY TESTS IN ANIMALS [S6]
a. You have to know that the toxic agent produces the same toxic effect with the same mechanism in the animal
as it does in humans. (This isn’t much of a problem to determine.)
b. It is generally necessary to eliminate risk at lower doses by extrapolating from data on higher doses.
1. This is particularly obvious, for example, in the case of a carcinogen, which might produce cancer at
a rate of only 1 in 10,000. So, exposure to high doses is needed to assess risk at low doses. This is
not readily possible though. It involves a lot of extrapolation, which can lead to mistakes and
misinformation.
2. This is why understanding the mechanism of action is so important in assessing risk. This can be
illustrated, for example, by the toxic effect of gamma radiation. (Is there a threshold level of gamma
radiation that doesn’t predispose someone to cancer?) The toxicological studies of radiation, many of
which were done on fruit flies, indicate that there is not threshold level; any exposure to gamma
radiation is potentially mutagenic and carcinogenic.
DOSE-RELATED TOXICITY [S7]
a. Most toxicity is dose-related (exception: allergic reactions).
b. It can be local (at the site of exposure). Or it can be disseminated throughout the body and have a systemic
effect.
c. The response may be immediate or delayed, reversible or irreversible.
d. Usually, a poison chiefly affects just a few organs. It is not always at the site of highest accumulation.
1. Example: lead poisoning
a. The CNS is most susceptible to lead poisoning (especially in children, because it is rapidly
growing). The CNS, though, is probably not the highest accumulation; the highest
accumulation of lead poisoning is probably in the bones (where it is accumulated long term).
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 10, 2010
Proof:
PROFESSOR: Smith
PRINCIPLES OF TOXICOLOGY
Page 2 of 5
b. By the way: The CNS is also susceptible to many other poisons.
2. Of course, poisoning does occur at other sites too. Example: methanol poisoning
a. Methanol, at higher levels, is sufficient to cause death. Even lower levels of poisoning can
cause blindness.
b. Many other toxic agents like methanol have a very specific effect at a very specific site in the
body.
VIII.
ACUTE POISONING [S8]
a. Acute poisoning is not a special medical emergency. It is treated as any other medical emergency though.
The exposure to the poison should be eliminated and supportive care should be given (make sure airways
are open, make sure the heart is beating, etc.).
b. Once stabilized, the amount of the poison in the crucial tissues should be minimizes.
c. Finally, administer an antidote (if available).
IX.
DECREASE ABSORPTION OF THE POISON [S9]
a. To decrease absorption, here is a list of what may be done. (The first one is not used as much today.)
1. Use activated charcoal (which adsorbs organic chemicals, and bring them out of the stomach). In
some cases, this is very difficult.
a. Example: iron supplements
b. This is a significant risk for poisoning in children because iron supplements typically have a
sweet taste (and children may mistake it for candy).
c. Once the iron supplements get into the stomach, a large mass forms, which is difficult to get
out of the stomach.
d. Hemodialysis is sometimes used. In other cases, surgery may be needed.
X.
CARBON MONOXIDE (CO) POISONING [S10]
a. Carbon monoxide is still a problem in the US.
b. A survey indicated that 11 of 10,000 ER patients had unexpectedly high carbon monoxide levels in their
blood. It’s easy for appliances to “leak” carbon monoxide in the gas-using homes.
c. Carbon monoxide is colorless, odorless gas that is a product of incomplete combustion.
d.
e.
XI.
CARBON MONOXIDE (CO) POISONING [S11]
a. Carbon monoxide has a very high affinity for hemoglobin than oxygen.
b. CO, even at low concentrations, is able to displace oxygen.
c. Graph
1. The higher curve: 100% oxygen hemoglobin
2. The dotted line: 50% anemia, 50% normal levels of hemoglobin in the blood
3. The lower line: 50% CO saturated hemoglobin
4. In normal hemoglobin, the concentration of oxygen (P O2) drops from 100 mmHg to 40 mmHg. The
blood then delivers 5 mL of oxygen.
5. With 50% CO saturated hemoglobin, the tissue concentration of oxygen drops from 100 mmHg to 10
mmHg; there is a great impairment in the capacity to deliver oxygen to the tissue. It’s “suffocation”
without warning. You feel “fine”, but you just feel like going to sleep (and may not wake up).
d. Treatment
1. Very simple process
2. It can be diagnosed by cherry red color of the blood, pink skin (because the CO hemoglobin is pink),
etc.
XII.
CARBON MONOXIDE (CO) POISONING [S12]
a. If a patient has CO poisoning and is unconscious, they need to be placed in a hyperbaric medicine chamber.
XIII.
THE HYPERBARIC MEDICINE DEPARTMENT [S13]
a. The hyperbaric medicine chamber give the CO poisoned patient 100% oxygen (at elevated atmospheric
pressure). This forces the oxygen onto the hemoglobin, displacing the CO. If done rapidly, the patient may
survive.
XIV.
CYANIDE (CN) POISONING [S14]
a. Symptoms: bright red blood (because CN blocks the utilization of oxygen in the tissues, so the hemoglobin is
stays saturated).
XV.
TREATMENT OF CYANIDE POISONING [S15]
a. CN binds to the cytochrome oxidase complex of the respiratory chain of mitochondria
b. CN blocks respiratory and oxygen utilization of mitochondria
c. Two antidotes:
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 10, 2010
Proof:
PROFESSOR: Smith
PRINCIPLES OF TOXICOLOGY
Page 3 of 5
1. Sodium nitrite (which displaces the cyanide from the iron in the cytochrome oxidase of the
respiratory chain)
2. Sodium thiosulfate (which reacts with the CN to produce thiocyanide, which is non-toxic and is then
rapidly excreted)
d. Both antidotes have to be administered very rapidly.
XVI.
ALTER BIOTRANSFORMATION AND EXCRETION OF THE POISON [S16]
a. In the case of methanol poisoning, metabolism of the methanol needs to be inhibited (because the blindness
caused by methanol poisoning is caused by a toxic metabolite of methanol, called formic acid).
b. There is drug for blocking the methanol metabolism. We’ll discuss later.
c. In the case of acetaminophen, metabolism doesn’t need to be blocked. In fact, the metabolism needs to be
completely metabolized to a non-toxic form (that is readily excreted).
XVII. METHANOL POISONING [S17]
a. Methanol is metabolized by alcohol dehydrogenase to produce formaldehyde. The formaldehyde is further
metabolized by another enzyme, aldehyde dehydrogenase, to the toxic metabolite, formic acid.
b. Results of methanol poisoning:
1. Visual disturbances
2. Acidosis
3. Coma
4. Death
c. The antidote that blocks these metabolic steps is a drug called 4-methylpyrazole (also known as fomepizole
or antizole).
d. If methanol poisoning is blocked, the methanol will not produce formic acid (and blindness), and the methanol
will be excreted (and the patient should be okay).
e. Before the use of 4-methylpyrazole, hemodialysis was used. Ethanol was also used against methanol
poisoning (as the enzymes would be saturated by ethanol so that they don’t metabolize the methanol).
XVIII. ETHYLENE GLYCOL POISONING CAUSES RENAL FAILURE [S18]
a. Ethylene glycol is the commonly used agent in antifreeze.
b. Animals (pets) sometimes drink this on accident. People have been known to drink this on accident too.
c. It is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. It doesn’t produce formic acid
(and blindness); it produces calcium oxalate, which is an insoluble salt that precipitates in the urine (shown by
crystal-like structures seen in the urine).
d. Ethylene glycol contains a chemical that is fluorescent. Because of this, an UV light can help determine if
ethylene glycol is present in the urine (and hopefully diagnose ethylene glycol poisoning more quickly).
e. The antidote: 4-methylpyrazole (the same antidote used for methanol too).
XIX.
ACETAMINOPHEN (APAP, TYLENOL, OTHER BRAND NAMES) [S19]
a. Acetaminophen poisoning is relatively common. 800 people per year have liver failure due to acetaminophen
poisoning (and about a third of those people die).
b. Acetaminophen poisoning occurs at about 2x or 3x more than the suggested daily dose.
c. Acetaminophen is metabolizes through an intermediate (toxic intermediate) in a PQI. This toxic intermediate
is further metabolized by conjugation to glutathione (via glutathione s-transferases, which is a drug
metabolizing enzyme, also known as GSTs).
XX.
ACETAMINOPHEN [S20]
a. Acetaminophen poisoning doesn’t cause liver damage until the liver cells become depleted of glutathione
(which is the cell’s major protective reducing agent).
b. Why? Because when the cells are continually exposed to high levels of acetaminophen, they become
depleted of glutathione. This impairs acetaminophen metabolism, and the toxic metabolite accumulates and
damages the liver cells.
XXI.
NO TITLE [S21]
XXII. ACETAMINOPHEN [S22]
a. Acetaminophen poisoning antidote: N-acetylcysteine (which is an acetyl group bound to the amino group of
the naturally occurring amino acid, cysteine).
b. Cysteine is a component of glutathione (which is a 3 amino acid compound, with the structurally middle amino
acid being cysteine).
c. By administering N-acetylcysteine, readily absorbable, usable cysteine is being administered (which works
much better than cysteine itself).
XXIII. ORGANIC SOLVENTS [S23]
a. Because we need to talk about the metals (arsenic, lead, mercury,), we’re going to skip this slide. You should
look at this information on your own.
XXIV. SUPERFUND AMENDMENTS AND REAUTHORIZATION ACT [S24]
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 10, 2010
Proof:
PROFESSOR: Smith
PRINCIPLES OF TOXICOLOGY
Page 4 of 5
XXV. METALS [S25]
a. Metals were the first obtainable (in relatively pure form) drugs. They were “early” drugs in the middle ages.
b. They are constituents of organic compounds.
c. We have evolved mechanism (like many other organism) for combating metal poisoning.
d. Humans have a protein called metalothionine (which binds metals and prevents them from producing damage
to cells).
XXVI. ARSENIC POISONING [S26]
a. Arsenic poisoning occurs in a variety of forms (depending on the chemical form of the arsenic). We will mainly
talk about arsenite poisoning. There are other forms of arsenic poisoning though. You could be exposed to
arsen gas though, for example.
b. It’s important to know what type of arsenic poisoning so that it can be treated effectively.
c. Poisoning toxicity is proportional to accumulation in the body.
d. It is metabolized in the liver and mostly eliminated in the urine.
XXVII. ARSENIC IS A CARCINOGENIC METAL [S27]
a. The public health concern: it is a carcinogenic metal. It accumulates in the skin and can cause skin, bladder,
lung, and liver cancer.
b. The problem: well water in Western US and Asia, for example, contains relatively high levels of arsenic. So if
people drink this well water over the course of many years, they substantially increase their chance of having
cancer or cardiovascular disease.
c. There is a concern that there may be an epidemic of cancer caused by arsenic (in drinking water,
particularly).
XXVIII. ARSENIC POISONING [S28]
a. Arsenic poisoning symptoms:
1. Accumulation in the skin, fingernails (may appear as white lines)
b. Arsenic poisoning treatment:
1. Chelation therapy with succimer
XXIX. ARSENIC POISONING [S29]
a. Arsenic is relatively tasteless.
b. Arsenic poisoning is not difficult to diagnose.
XXX. ARSENITE (+3) AND ORGANIC ARSENICALS [S30]
a. Arsenite interacts with sulfhydryl groups.
b. It impairs the delivery of carbon intermediates to the respiratory chain by reacting with a cofactor of the
enzymes (called lipoamide).
c. Arsenic generally blocks the generation of ATP.
d. Arsenate is a phosphate analog. It also blocks the generation of ATP.
e. The major points: long-term exposure to arsenic (which is sometimes received from drink well water). This
may predispose someone to cancer or cardiovascular disease. For acute poisoning, chelate thrapy with
succimer is best (although this may not be as helpful in long term poisoning).
f. Nothing more about arsenic poisoning will be said. You may review it yourself. We need to move on to lead
poisoning.
XXXI. ARSENITE (+3) AND ORGANIC ARSENICALS [S31]
XXXII. ARSENATE (+5) IS A PHOSPHATE ANALOG [S32]
XXXIII. ARSENATE METABOLISM TO DIMETHYL ARSENITE [S33]
XXXIV. LEAD (Pb) POISONING [S34]
a. Lead is ubiquitous in the environment. Lead is no long an additive to gasoline (because that was a major risk
for exposure for the public).
b. Lead binds hemoglobin.
c. Major sites of toxicity (which are not the highest locations of accumulation)
1. Heme synthesis in mitochondria
2. CNS (which disrupts all CNS functions and is often irreversible)
XXXV. LEABE (Pb) IN PAINT [S35]
a. Lead is used in paint (on vinyl lunch boxes, backpacks, costumes, toys, etc.)
XXXVI. MECHANISM OF LEAD (Pb) TOXICITY [S36]
a. How do you know if lead toxicity is present? The blood lead level must be measured.
b. The best method to reducing lead poisoning: find the source of the lead poisoning, then eliminate it.
XXXVII. HEME SYNTHESIS [S37]
a. Another symptom: accumulation of an intermediate of heme synethesis (namely, aminolevulinic acid).
XXXVIII. CDC’S ACTION LEVEL OF BLOOD LEAD IN CHILDREN [S38]
a. The CDCs concern of action level of lead in children’s blood has continually decreased.
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 10, 2010
Proof:
PROFESSOR: Smith
PRINCIPLES OF TOXICOLOGY
Page 5 of 5
b. It occurs everywhere! But we are reducing it, at least.
c. Much of the reduction (shown here) is correlated to the elimination of leaded gasoline.
XXXIX. PHASE OUT OF LEADED GASOLINE IN US [S39]
XL.
LEAD (Pb) POISONING [S40]
XLI.
LEAD (Pb) POISIONING SYMPTOMS [S41]
a. Symptoms (many of which are vague):
1. Headache
2. Abdominal pain
3. Vertigo
4. Dizziness
5. Restlessness
b. The key diagnostic instrument: blood lead level measurement
XLII.
MINAMATA [S42]
a. Epidemic of mercury poisoning in Japan
XLIII. “TO CAUSE AWARENES IS OUR ONLY STRENGTH” [S43]
XLIV. ALABAMA POWER’S MILLER STEAM PLANT [S44]
a. Mercury poisoning is also a public concern in Birmingham
b. There is a plant on the Westside of Jefferson County that puts off more mercy in the air than any other power
plant in the nation. With the help of many advocates, this will eventually stop.
XLV. THE BIRMINGHAM NEWS [S45]
XLVI. MERCURY (Hg) POISONING [S46]
a. Mercury is metabolized by microbes (in soil, rivers, lakes).
b. It is methylated. It is lipid-soluble.
c. It accumulates further up the food chain.
d. Traces of mercury have been found in fish (especially larger fish). This is a cautionary warning. (It is also an
environmental concern, as it may affect the food chain.)
XLVII. MERCURY (Hg) MOUTH [S47]
a. The amalgams are about 50% mercury. They are very effective. They have been used for a long time. The
produce no appreciable toxicity. There is, however, a great concern though, as it can be another source of
mercury.
b. Many children are poisoned – maybe not by raw fish, but by tuna from the store, which is 1 ppm mercury. The
more tuna in a diet, the greater the chances of mercury poisoning.
XLVIII. FASEB [S48]
a. In this study, people were told not to eat seafood. The level of mercury in the urine was measure. To do this
efficiently, oral succimer was administered. When the mercury came out of the amalgam, it vaporizes and is
released into the blood, where it binds succimer. The succimer-mercury complex, then, is excreted in the
urine. For completion, the study did this for a variety of people who had different amounts of amalgam. There
was a direct correlation: the greater the amalgams on the grinding teeth, the greater the mercury excreted.
XLIX. MERCURY (Hg) POISONING [S49]
L.
CORPORATIONS SPREAD MISINFORMATION [S50]
LI.
WHY I CARE ABOUT THE ENVIRONMENT? [S51]
LII.
METALLOTHIONEIN [S52]
a. The body does have the ability to detoxify metallothionein.
LIII.
METAL CHELATION THERAPY [S53]
LIV.
CALCIUM SODIUM EDTA [S54]
LV.
DIMERCAPTOSUCCINIC ACID (SUCCIMER) [S55]
LVI.
SUCCIMER [S56]
a. Succimer binds the metal via sulfur atoms (in the succimer).
b. It is orally effective.
c. It doesn’t deplete the body of healthy (essential) levels of metals.
d. The succimer does not release the metal into the urine (as does the previous chelater, EDTA)
e. It’s not perfect though: it doesn’t enter cells.
f. It is effective against lower levels (not higher levels).
LVII.
TOXICOLOGY [S57]
a. Summary:
1. Toxicity is proportional to dose or exposure. It usually occurs by a specific mechanism. Understand
the mechanism (as it helps in the development of antidotes and aids in the assessment of risk).
2. The goal: minimize exposure and administer a specific antidote (if available).
[End 56:00 mins]